1. Field of Invention
The present invention relates to a novel polymorph of Quetiapine fumarate and a process for its preparation. The novel polymorph of quetiapine fumarate of the present invention has been designated by us as Form IV. The quetiapine fumarate is salt of 2-[2-(4-dibenzo [b,f]][1,4] thiazepin-11-yl-1-piperazinyl) ethoxy]-ethanol with fumaric acid (2:1). It is also referred as hemifumarate in some patent literature. Its complete structure is shown below:
Quetiapine fumarate is a well known anti psychotic agent useful in treating schizophrenia and other CNS disorders.
2. Description of Related Art
U.S. Pat. No. 4,879,288 discloses a process for the preparation of Quetiapine hemifumarate. According to this patent, a crystalline quetiapine hemifumarate is prepared by treating ethanolic solution of Quetiapine free base with fumaric acid. The compound was characterized only by its melting point (172-173° C.) and C,H,N analysis. No other characteristics have been described in the '288 patent. However, the authors of a later patent application US 2003/0216376 have prepared the same compound by the method described in the '288 patent and characterized the same additionally with XRD and FT-IR data, at the same time designating it as Form I. Although the '376 application is accompanied by FIGS. (9 & 10) of XRD and FTIR of the “Form I”, data are not quoted by the authors. Our attempt to produce the crystalline form of quetiapine hemifumarate as described in ‘288’ patent and showing characteristics of “Form I” failed. The XRD and FT-IR data of the product prepared by the above mentioned process, from several experiments confirmed that the procedure described in '288 patent does not yield consistent product.
U.S. Patent Application No. 2003/0216376A1 describes two new polymorphs of quetiapine hemifumarate besides their solvate forms. The two new polymorphs are designated Forms II and III by the authors.
Form II is prepared by treating quetiapine hemifumarate with chlorinated solvents. Form II solvate of chloroform is obtained when the chlorinated solvent is chloroform and Form II solvate of methylene chloride is obtained when the chlorinated solvent is methylene chloride.
Form III is prepared by treating quetiapine hemifumarate solution in an aprotic solvent with chloroform and stirring the resulting mixture for a period of at least 14 hours. Form III is obtained as solvate of chloroform.
The characteristics of the two new forms II and III as given in the '376 patent application are shown in table I below:
TABLE IXRD −2θ ValuesFT - IR cm−1DSC peaks° C.Form II7.8, 11.9, 12.5639, 1112, 1395,130 and(′376)15.7, 23.0, 23.41616, 1711, 3423166Form III8.9, 11.8, 15.3748, 758, 1402,111, 142 and(′376)19.4, 23.0, 23.41607, 1715, 2883167
Only the '288 patent and '376 patent application refer to the compound as ‘hemifumarate’ salt whereas all other standard literature refer it simply as “fumarate.” In the rest of this document the name “quetiapine fumarate” is retained and is inclusive of the alternate name of “quetiapine hemifumarate.”
WO 2004/078735 also describes two new crystalline polymorphs of quetiapine fumarate, characterized by its XRD pattern. The U.S. Patent Application No. US 2003/0216376A1 was filed on Mar. 20, 2003 and published on Nov. 20, 2003. WO 2004/078735 was filed on Mar. 3 ,2003 before the publication of the '376 application. The authors of the '735 patent application have also chosen to name their new polymorphs as “Form I and II.” This has led to some confusion. However, the '735 forms I and II clearly differ from the '376 forms II and III. The '735 application records only the XRD data of the “Forms I & II”. The data given in the '735 application is shown below in table II. Neither the FT-IR nor the DSC data for these new forms are provided.
TABLE IIXRD Data (2θ values) as given in ′735 patent applicationForm IForm II7.3, 9.2, 11.6, 13.3, 14.4,4.9, 7.4, 9.2, 11.7, 13.4, 14.4, 14.9, 15.4,14.8, 15.3, 15.9, 16.2, 16.7,15.9, 16.3, 16.7, 17.7, 18.6, 19.8, 20.2,17.6, 19.1, 19.7, 20.1, 20.8,20.8, 21.2, 21.9, 22.4, 22.9, 23.4, 24.3,21.1, 21.8, 22.3, 23.4, 24.3,24.7, 25.2, 25.7, 26.9, 27.8, 28.8, 29.4,24.7, 25.1, 25.6, 27.1, 28.5,33.2, 35.9, 38.0, 38.7, 39.9 and 42.829.5, 33.2 and 40.4
According to WO 2004/078735, Form I is prepared by dissolving quetiapine free base and fumaric acid in a suitable solvent such as acetone, isobutyl ketone, ethyl acetate, ethyl formate, or methyl acetate by heating. On cooling the solution to about 25° C., crystals of Form I are obtained.
Form II is obtained by dissolving quetiapine in methyl tert.butyl ether and adding fumaric acid to the quetiapine solution at reflux temperature. On cooling the solution to about 25° C., crystals of Form II are obtained.
Form I and Form II obtained by the methods described in '735 application seem to differ from the Forms II and III obtained according to the US patent application Ser. No. US 2003/0216376A1 in their XRD patterns.
In addition to the two new crystalline polymorphs the PCT application No. WO 2004/078735 also describes an amorphous form of quetiapine fumarate. The authors have not designated it by any trivial name but refer to it simply as “amorphous form.” It is obtained by dissolving quetiapine fumarate in a solvent mixture containing methanol and chloroform and vacuum drying, as per the '735 application.
The amorphous form is characterized by powder XRD pattern having maximum expressed as 2θ at about 10° to about 30°. The accompanying diagram in the patent application displays a series of maxima as claimed.
All the existing polymorphs, as explained above, are obtained using chlorinated solvents such as chloroform and methylene chloride. Both chloroform and methylene chloride are known carcinogens (CRC Handbook of Laboratory Safety, Edited by A. Keith Furr, CRC Press, Boca Raton, 4th Edition, 1995, pg 217-564). (Merck Index, Merck & Co. Inc, USA, Entry 2160, 13th Edition, 2001) Chloroform is also banned by FDA from use in drug, cosmetic, and food packaging products. Both chloroform and methylene chloride are designated as Class 2 solvents under International Conference on Harmonisation (ICH) because of their inherent toxicity. (ICH guidelines for residual solvents, 1997).
The solvate polymorphs of Forms II and III obtained as per the U.S. Patent Application No. U.S. 2003/0216376A1 contain chlorinated solvents, hence hazardous to health. The amorphous form of Quetiapine fumarate prepared by the method of WO 2004/078735 also uses the undesirable chloroform.
All references cited herein are incorporated herein by reference in their entireties.